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PEGylated Liposomes Accumulate in the Areas Relevant to Skin Toxicities Passive Extravasation across "Leaky" Endothelium. | LitMetric

AI Article Synopsis

  • PEGylated liposomes are critical in drug delivery but can cause harmful skin toxicity, as seen with PEGylated liposomal doxorubicin (Doxil).
  • Research using imaging techniques in mice reveals that these liposomes accumulate in areas under mechanical stress, particularly in the skin of the feet, due to leaky blood vessels.
  • The study identifies two ways liposomes escape blood vessels—either as whole liposomes or as separate components—highlighting a passive diffusion process rather than active cellular mechanisms, paving the way for better management of related skin toxicities.

Article Abstract

PEGylated liposome is the cornerstone platform for modern drug delivery. Unfortunately, as exemplified by PEGylated liposomal doxorubicin (aka Doxil), altered doxorubicin pharmacokinetics causes off-target accumulation in the skin, including the palms and feet, leading to severe dose-limiting toxicity. In addition to Doxil, other nanoparticles and PEGylated liposomes exhibit significant deposition in the skin, but mechanisms of accumulation are poorly understood. Using imaging and confocal microscopy, we show that PEGylated liposomes in mice accumulate predominantly in the areas subject to mechanical stress/pressure. Blood vessels in foot skin appear to be especially leaky, exhibiting burst-like extravasations. Using high-resolution confocal microscopy and liposomes labeled with different dyes in the membrane and/or interior, two modes of extravasation were observed: (1) as intact liposomes; (2) as separated liposomal components. On the other hand, stable cross-linked iron oxide nanoworms extravasated only as intact nanoparticles. There was no colocalization between liposomes and exosomal marker CD81, excluding the role of exocytosis. Also, perfusion of formalin-fixed foot skin with labeled liposomes revealed that the extravasation is mediated by passive, energy-independent diffusion and not by leukocyte "hitchhiking". These findings improve our understanding of extravasation pathways of nanocarriers in the areas relevant to skin pathologies and could lead to strategies to prevent and treat liposome-induced skin toxicities.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10472601PMC
http://dx.doi.org/10.1021/acsnano.2c00423DOI Listing

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